Streptococcus pyogenes, the group A streptococcus (GAS) is an important human pathogen causing frequent self-limiting diseases which may lead to serious sequelae. In addition, the GAS seems to be "reemerging" as a cause of life-threatening invasive disease. Because of the great diversity of syndromes produced by many strains of GAS, we wish to improve our understanding of the pathogenesis of this organism by focusing on the regulation of expression of its genes, which presumably occurs on interaction with the human host to determine disease outcome. This proposal focuses on the two major global regulators that alter expression of many GAS proteins, including virulence factors. The regulation of expression of Mga (Aim 1) and CovR/S (CsrR/S) (Aim 3) will be studied. The genes controlled by Mga and CovR/S and the mechanisms by which these regulatory proteins control expression of these genes will also be investigated (Aims 2 and 4). We hope these analyses will improve our understanding at the molecular level of the interactions of GAS with its human host and may identify new targets for development of therapies and vaccines.